Fungal infections are a huge clinical burden and highly prevalent among compromised host populations worldwide. Fungal pathogens in humans cause both superficial mucosal and systemic mycoses with higher morbidity and mortality rates. For instance, recent studies including ours, indicated that mortality rate of systemic candidiasis among hospitalized patients could be as high as 70% under compromised conditions. Treatment for fungal infections, including hospital stay, is costly.
During last couple of years fungal infection has become a major threat to hospitalized patients worldwide. In particular, Candida is the major fungal pathogen in humans which cause millions of mucosal and systemic mycoses worldwide. Despite the currently available antifungal agents, Candida remains to be the ubiquitous pathogen causing severe mucosal infections such as oral candidiasis, onycomycoses (nails), vulvovaginal candidiasis as well as systemic mycoses. Hence, candidiasis is a leading cause of hospital-acquired infection, surpassing most bacterial infections. Unlike most bacterial diseases, fungal diseases are difficult to treat. Hence, there is higher mortality associated with systemic candidiasis. Local data from Hong Kong indicate mortality of systemic candidiasis in hospital settings could be as high as 70%. Rising drug resistance for available drug as indicated global surveys is a major problem for treating fungal infections. Development of more effective antifungal drugs with lesser side effects has become a highest priority in the field. Therefore, novel antifungal compounds with such desirable properties will be of great clinical importance. Compromised host populations such as HIV/AIDS patients, organ transplant recipients, patients on chemotherapy are expected to rise over next decade and those groups are highly prone to fungal infections with serious consequences. Therefore, there is an increasing demand for antifungal agents that have excellent inherent pharmacokinetic characteristics and potent inhibitory activities against a broad spectrum of fungi. Although there are several classes of antifungal agents are currently available, none of them, however, are sufficiently satisfactory for use as medicine in that they do not exhibit all of excellent inhibitory activity against some of the opportunistic fungi which cause fatal infections and suitable pharmacokinetics within the body.
The fungal pathogen Candida species are common causes of opportunistic and systematic infection, which may be lethal in immunodeficient individuals including those HIV-infected and radio- or chemo-therapy recipients. Candida albicans is the most prevalent Candida species isolated from human hosts. It lives as a commensal in skin, oral cavity and esophagus, gastrointestinal tract, vagina and vascular system and causes disease when given the opportunity. Candida albicans is able to switch between the yeast and the hyphal form, thus combining the better dispersal properties of the yeast form with the invasive properties of the hyphal form. The hyphae can penetrate the epithelium into the host cell to acquire nutrients for fungi, resulting in invading or damaging these tissues or organs. The reversible morphological transitions into hyphal growth forms can further enhance C. albicans' virulence.
Usually Candida spp. resides in a mixed habitation with other microbial. Such habitation is biofilm. In biofilms, the inhabitants (mainly fungi and bacteria) are encapsulated into a matrix of glycoproteins and polysaccharides produced by themselves and they usually reside with low metabolic activity. Through biofilm, Candida can adhere to denture, implanted medical device (including catheter and heart valves) and tissue surfaces, denture and host organs with strong resistance to anti-fungal treatment. This makes the Candida infection hard to treat. On the other hand, the various virulent inhabitants within the biofilm are more harmful than single Candida population. As a result, an implanted device is always associated these infections and a biofilm can be detected on the surface of the device. Candida spp. becomes common pathogen and is regarded as agents of nosocomial pneumonias and urinary tract infections, without effective treatment. Despite increasing numbers of health-compromised people, who are prone to contracting life-threatening fungal diseases, only a few classes of anti-fungal drugs, such as polyenes, azoles, echinocandins, allylamines, and flucytosine, are available for the treatment of fungal infections.
However, polyenes have dose-related toxicity, particularly nephrotoxicity, although the introduction of lipid formulations has improved risk-benefit ratio. In addition, rising drug resistance is an inevitable problem. Emergence of drug-resistant strains to fluconazole, a drug of choice for AIDS patient has become a major problem, although second-generation triazoles have addressed some issues (Fera M T, La Camera E, De Sarro A. New triazoles and echinocandins: mode of action, in vitro activity and mechanisms of resistance. Expert Rev Anti Infect Ther. 2009; 7(8):981-98. Therapeutic failures and emergence of resistance have already been reported for recently introduced echinocandin antifungal agents. As a result of the limitations of existing antifungal agents, mortality rates for candidemia remain high. This situation highlights the urgent need for more effective and safer antifungal agents for this ubiquitous fungal infection, for example, recalcitrant Candida infection.